VCIP135 acts as a deubiquitinating enzyme during p97–p47-mediated reassembly of mitotic Golgi fragments

Wang, Yanzhuang; Satoh, Ayano; Warren, Graham; Meyer, Hemmo

doi:10.1083/jcb.200401010

Cited by 143 publications

(169 citation statements)

References 28 publications

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“…10B). In addition to its role in ERAD, and in conjunction with its p47 and VCIP135 effectors, VCP regulates homotypic ER and Golgi membrane fusion, which reconstitutes the membranes of these organelles following their disassembly during cell division (71)(72)(73). In the absence of VCP following cell division, ER transition vesicles may have been unable to fuse to reconstruct normal ER architecture (74).…”

Section: Sirna Knockdown Of Vcp Markedly Changes the Architecture Of mentioning

confidence: 99%

Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade

Mimnaugh

Vos

et al. 2006

Molecular Cancer Research

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Geldanamycin and Velcade, new anticancer drugs with novel mechanisms of action, are currently undergoing extensive clinical trials. Geldanamycin interrupts Hsp90 chaperone activity and causes down-regulation of its many client proteins by the ubiquitin-proteasome pathway; Velcade is a specific proteasome inhibitor. Misfolded Hsp90 clients within the endoplasmic reticulum (ER) lumen are cleared by ER-associated protein degradation, a sequential process requiring valosin-containing protein (VCP) -dependent retrotranslocation followed by ubiquitination and proteasomal proteolysis. Cotreatment of cells with geldanamycin and Velcade prevents destruction of destabilized, ubiquitinated Hsp90 client proteins, causing them to accumulate. Here, we report that misfolded protein accumulation within the ER resulting from geldanamycin and Velcade exposure overwhelms the ability of the VCP-centered machine to maintain the ER secretory pathway, causing the ER to distend into conspicuous vacuoles. Overexpression of dominantnegative VCP or the ''small VCP-interacting protein'' exactly recapitulated the vacuolated phenotype provoked by the drugs, associating loss of VCP function with ER vacuolization. In cells transfected with a VCP-enhanced yellow fluorescent protein fluorescent construct, geldanamycin plus Velcade treatment redistributed VCP-enhanced yellow fluorescent protein from the cytoplasm and ER into perinuclear aggresomes. In further support of the view that compromise of VCP function is responsible for ER vacuolization, small interfering RNA interference of VCP expression induced ER vacuolization that was markedly increased by Velcade. VCP knockdown by small interfering RNA eventually deconstructed both the ER and Golgi and interdicted protein trafficking through the secretory pathway to the plasma membrane. Thus, simultaneous geldanamycin and Velcade treatment has far-reaching secondary cytotoxic consequences that likely contribute to the cytotoxic activity of this anticancer drug combination. (Mol Cancer Res 2006;4(9):667 -81)

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Section: Sirna Knockdown Of Vcp Markedly Changes the Architecture Of mentioning

confidence: 99%

Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade

Mimnaugh

Vos

et al. 2006

Molecular Cancer Research

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“…The VIM of gp78 interacts with the ND1 domain of p97/VCP, the reported binding site for SVIP, Ufd1, and p47, another p97/ VCP cofactor required for Golgi and ER membrane fusion (22,23). SVIP, Ufd1, and p47 are known to bind p97/VCP in a mutually exclusive manner.…”

mentioning

confidence: 99%

The Role of a Novel p97/Valosin-containing Protein-interacting Motif of gp78 in Endoplasmic Reticulum-associated Degradation

Ballar

Shen

Yang

et al. 2006

Journal of Biological Chemistry

118

155

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Improperly folded proteins in the endoplasmic reticulum (ER) are eliminated via ER-associated degradation, a process that dislocates misfolded proteins from the ER membrane into the cytosol, where they undergo proteasomal degradation. Dislocation requires a subclass of ubiquitin ligases that includes gp78 in addition to the AAA ATPase p97/VCP and its cofactor, the Ufd1-Npl4 dimer. We have previously reported that gp78 interacts directly with p97/VCP. Here, we identify a novel p97/ VCP-interacting motif (VIM) within gp78 that mediates this interaction. We demonstrate that the VIM of gp78 recruits p97/ VCP to the ER, but has no effect on Ufd1 localization. We also show that gp78 VIM interacts with the ND1 domain of p97/VCP that was shown previously to be the binding site for Ufd1. To evaluate the role of Ufd1 in gp78-p97/VCP-mediated degradation of CD3␦, a known substrate of gp78, RNA interference was used to silence the expression of Ufd1 and p97/VCP. Inhibition of p97/VCP, but not Ufd1, stabilized CD3␦ in cells that overexpress gp78. However, both p97/VCP and Ufd1 appear to be required for CD3␦ degradation in cells expressing physiological levels of gp78. These results raise the possibility that Ufd1 and gp78 may bind p97/VCP in a mutually exclusive manner and suggest that gp78 might act in a Ufd1-independent degradation pathway for misfolded ER proteins, which operates in parallel with the previously established p97/VCP-Ufd1-Npl4-mediated mechanism.

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“…Shp1 (p47) possesses a UBA ubiquitin binding domain in its N terminus and forms a complex with Cdc48 to facilitate membrane fusion and possibly proteasomal degradation (15,25,39). Also involved in the membrane fusion process is VCIP135, a deubiquitinating enzyme that interacts with the p97-p47 complex and is necessary for Golgi membrane reassembly (43,46). Ufd1-Npl4 binds to ubiquitin via the NZF ubiquitin binding domain present in Npl4 (30,45).…”

mentioning

confidence: 99%

Doa1 Is a Cdc48 Adapter That Possesses a Novel Ubiquitin Binding Domain

Mullally

Chernova

Wilkinson

2006

Molecular and Cellular Biology

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Cdc48 (p97/VCP) is an AAA-ATPase molecular chaperone whose cellular functions are facilitated by its interaction with ubiquitin binding cofactors (e.g., Npl4-Ufd1 and Shp1). Several studies have shown that Saccharomyces cerevisiae Doa1 (Ufd3/Zzz4) and its mammalian homologue, PLAA, interact with Cdc48. However, the function of this interaction has not been determined, nor has a physiological link between these proteins been demonstrated. Herein, we demonstrate that Cdc48 interacts directly with the C-terminal PUL domain of Doa1. We find that Doa1 possesses a novel ubiquitin binding domain (we propose the name PFU domain, for PLAA family ubiquitin binding domain), which appears to be necessary for Doa1 function. Our data suggest that the PUL and PFU domains of Doa1 promote the formation of a Doa1-Cdc48-ubiquitin ternary complex, potentially allowing for the recruitment of ubiquitinated proteins to Cdc48. DOA1 and CDC48 mutations are epistatic, suggesting that their interaction is physiologically relevant. Lastly, we provide evidence of functional conservation within the PLAA family by showing that a human-yeast chimera binds to ubiquitin and complements doa1⌬ phenotypes in yeast. Combined, our data suggest that Doa1 plays a physiological role as a ubiquitin binding cofactor of Cdc48 and that human PLAA may play an analogous role via its interaction with p97/VCP.

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VCIP135 acts as a deubiquitinating enzyme during p97–p47-mediated reassembly of mitotic Golgi fragments

Cited by 143 publications

References 28 publications

Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade

Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade

The Role of a Novel p97/Valosin-containing Protein-interacting Motif of gp78 in Endoplasmic Reticulum-associated Degradation

Doa1 Is a Cdc48 Adapter That Possesses a Novel Ubiquitin Binding Domain

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